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Imino sugar derivatives demonstrate potent antiviral activity and reduced toxicity

a technology of imino sugar and derivatives, which is applied in the field of antiviral compounds and compositions, can solve the problems of limited development of imino sugar glucosidase inhibitors, low efficacy and/or cytotoxicity, and misfolding and degradation of glycoproteins, and achieves low cytotoxicity, high inhibitory potency, and improved antiviral activity.

Inactive Publication Date: 2015-05-26
INST FOR HEPATITS & VIRUS RES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The PBDNJ compounds exhibit high potency and low toxicity, offering potential as therapeutic agents for flaviviral infections, with enhanced antiviral activity and improved safety profiles, and show synergistic effects when combined with ribavirin, providing effective treatment options for dengue and hepatitis C.

Problems solved by technology

Thus, inhibition of α-glucosidases leads to the misfolding and degradation of glycoproteins where this specific interaction is required.
The development of a imino sugar glucosidase inhibitor is limited by low efficacy and / or cytotoxicity.
More specifically, Dengue virus (DV) infection is a growing world health problem and a bio-terror concern.
Thus far, effective antiviral therapies and vaccines are not yet available to treat or prevent DV infection.
Moreover, the emergence of resistant virus would be expected to be rare.

Method used

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  • Imino sugar derivatives demonstrate potent antiviral activity and reduced toxicity
  • Imino sugar derivatives demonstrate potent antiviral activity and reduced toxicity
  • Imino sugar derivatives demonstrate potent antiviral activity and reduced toxicity

Examples

Experimental program
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Effect test

example 1

Introduction of Oxygenated and Terminal Ring Structures into the Nitrogen-Linked Alkylated Side Chain of Deoxynojirimycin

Materials and Methods

[0039]Cells and viruses. BVDV-free MDBK cells (CCL 22) were obtained from the American Type Culture Collection and propagated in DMEM / F12 essential medium supplemented with penicillin (500 U / ml), streptomycin (500 U / ml), and 10% heat inactivated horse serum (Invitrogen). Cells were maintained in a humidified incubator at 37° C. with 5% CO2. BVDV (NADL strain). For infections, virus inoculum was added in complete medium and adsorbed for 1 hour at 37° C., the inoculum was then removed, the cells washed once with medium and fresh medium containing compounds added. Virus stocks were prepared by freeze-thawing the infected cells and culture supernatant three times followed by centrifugation at 1,000 g for 5 min. Stock titers were determined, and stocks were aliquoted and stored at −80° C. WNV was obtained from a cDNA clone of a human 2002 isolate f...

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Abstract

Imino sugars, such as deoxynojirimycin (DNJ), are glucose analogues that selectively inhibit cellular α-glucosidase I and II (enzymes that process N-linked glycans in glycoprotein) and exhibit broad spectrum antiviral activities against many enveloped viruses. Previously we have reported a novel DNJ derivative, OSL-95II, with antiviral activity and reduced cytotoxicity. In order to develop imino sugars with more potent antiviral activity as well as improved toxicity profile, OSL-95II was modified by diversifying the nitrogen linked alkylated side chain. The antiviral activities were initially tested in bovine viral diarrhea virus (BVDV) infected MDBK cells, yielding several imino sugar derivatives with novel structure and superior antiviral activity and toxicity profile. Furthermore, these new compounds were shown to be active against Dengue virus (DV) and West Nile virus (WNV) infection in BHK cells where potent anti-DV activity having submicromolar EC50 values and SI of greater than 900. These compounds represent a new generation of iminio sugars and their analogues, having application in the clinical treatment of infection of DV and other members of flaviviridae.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a non-provisional application, the entire contents of which is incorporated by reference herein and claims priority, in part, of U.S. Provisional Application No. 61 / 190,618, filed 2 Sep. 2008 and International Application PCT / US2009 / 055658, filed 2 Sep. 2009.BACKGROUND[0002]1. Field[0003]This invention relates to the field of antiviral compounds and compositions for the treatment against flaviviral infections. More specifically, it relates to N-pentyl-(1-hydroxycyclohexyl)-DNJ derivatives and their use as pharmaceutical compositions in the treatment and prevention of Dengue, West Nile, Japanese Encephalitis virus, Bovine viral diarrhea virus, and hepatitis C.[0004]2. Background Art[0005]Imino sugars are broad-spectrum antiviral agents that interfere with virus assembly through glucosidase inhibition. Dengue virus has an envelope protein with a specific structure that makes it more sensitive to imino sugar treatment. Co...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D211/46A61K31/445A61K31/47A61K31/7056
CPCA61K31/47C07D211/46A61K31/7056A61K2300/00Y02A50/30
Inventor BLOCK, TIMOTHY M.CHANG, JINHONGXU, XIAODONG
Owner INST FOR HEPATITS & VIRUS RES
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